Project Summary/Abstract Malaria afflicts ~198 million people yearly, with 438,000 malaria deaths due to Plasmodium falciparum, underscoring the need for a highly effective malaria vaccine. The first licensed malaria vaccine, RTS,S, may provide much-needed reductions in morbidity and mortality, but its modest efficacy in reducing clinical malaria in the target population of African infants leaves ample margin for improvement. A better understanding of immunity to P. falciparum in naturally exposed populations can inform efforts to improve malaria vaccine design. To date, there are no reliable correlates of protection from either symptomatic P. falciparum infection (clinical immunity) or parasitemia (sterile immunity). Systems biology utilizes computational modeling of large- scale data sets to elucidate complex biological networks and has the potential to reveal novel predictors and mechanisms of malaria protection when applied to well-designed clinical cohort studies. In this project, the candidate proposes to assess immune predictors of natural protection from P. falciparum infection using systems biology approaches. By analyzing clinical data and blood specimens collected from a well-characterized, prospective cohort of Malian children who differ in their degree of immunity to P. falciparum infection, the candidate will address two main research aims: 1) determine immune parameters predictive of protection from symptomatic infection (clinical immunity) and protection from P. falciparum infection (sterile immunity) and 2) relate these immune parameters and outcomes to the ability of plasma obtained from these children to inhibit parasite invasion into liver and red blood cells in vitro. The practical implications of this work include identifying novel immune predictors and mechanisms of protection from P. falciparum infection and disease within the vaccine target population that could provide rational benchmarks for candidate malaria vaccines. The candidate is firmly committed to a career in translational malaria research and systems biology and is strongly supported in his career and research goals by his mentors and his division at the Indiana University School of Medicine. He currently holds a position as an Assistant Professor of Medicine with 80% protected time for research, independent laboratory and office space, and funding for equipment. The current proposal includes a comprehensive mentorship and didactic plan to advance the candidate's skills and knowledge in biostatistics and computational biology required for developing expertise in systems biology. Under the guidance of his primary mentor, Dr. Chandy John, and his co-mentors, Dr. Wanzhu Tu, Dr. Lang Li, and Dr. Peter Crompton, he will advance his bioinformatics skills and learn predictive modeling methodologies that will be directly applied to this proposal. Completion of this comprehensive training plan will provide the candidate with the skills and experience necessary to become a successful independent investigator specializing in computational systems biology with a focus on host immunity to Plasmodium infection.